Serotonin (5-hydroxy-tryptamine, 5-HT) receptors play an important role in many physiological functions as well as pathological disorders including but not limited to depression, generalized anxiety, eating disorders, panic disorder, sleep disorders, aggression, dementia and other cognitive dysfunctions. Furthermore, serotonin has been implicated in gastrointestinal disorders, cardiovascular regulation, motor disorders, endocrine disorders, vasospasm and sexual dysfunction. The 5-HT receptors are distributed throughout the body and can be divided into at least 14 different subtypes (Barnes and Sharp, Neuropharmacology, (1999) 38, 1083-1152). The various subtypes are responsible for serotonin's actions in many pathophysiological conditions. The 5-HT1 family of receptors has high affinity for serotonin and consists of five related receptors. This family includes the 5-HT1A, 5-HT1B and 5-HT1D receptor subtypes.
Compounds interacting with the 5-HT1 family are known to have therapeutic potential in the above-mentioned disorders and diseases. In particular, compounds which are 5-HT1A and 5-HT1B antagonists have been shown to improve cognitive function. Moreover, compounds which are 5-HT1A, 5-HT1B, and 5-HT1D antagonists have been shown to be antidepressant and anxiolytic agents. Compounds which are agonists at the 5-HT1B and 5-HT1D receptors, have been used in the treatment of migraine and could also be useful in the treatment of Parkinson's Disease.
Scientific research has revealed a potential therapeutic use for modulators of the 5-HT1A and the 5-HT1B receptors, especially with regard to various CNS disorders. Blocking 5-HT1A receptor function has been shown to enhance cholinergic transmission. Partial 5-HT1A agonists as well as 5-HT1A antagonists have been shown to increase the release of acetylcholine (J. Phamacol. Exp. Ther. 311 (2004), 190-203). 5-HT1A antagonists have also been shown in in vivo cognition models to reverse cognitive deficits induced by the muscarinic antagonist scopolamine (Carli et al, Eur. J. Pharmacol., 283 (1995), 133) or the NMDA antagonist MK-801 (Neurobiol. Learning and Memory, 71 (1999), 259; Neuropharmacology 39 (2000) 547-552). Blocking the 5-HT1B receptor has been shown in microdialysis experiments to increase the levels of acetylcholine in the frontal cortex and hippocampus of awake rats (Hu et al, Eur. Neuropsychopharmacology 17 (2007), 580-586) and have positive effects in cognition models (Åhlander-Luttgen et al, Neuropsychopharmacology (2003) 28, 1642-1655). Therefore, compounds that are partial agonists or antagonists of the 5-HT1A and/or 5-HT1B receptors should be useful in the treatment of cognitive disorders such as Alzheimer's disease.
Scientific research have shown that the use of 5-HT1B antagonists should be useful in the treatment of psychiatric disorders such as depression, anxiety, OCD (obsessive compulsive disorders) and other psychiatric disorders (Eur. J. Pharmacol. (2000), 404, 1-12).
5-HT1A antagonists have shown to be active in models of anxiety in non-human primates (Eur. J. Pharmacol. (2003) 482 197-203). Therefore, compounds that are partial agonists or antagonists of the 5-HT1A and/or 5-HT1B receptors should be useful in the treatment of psychiatric disorders such as depression, anxiety and OCD.